Hepatocellular carcinoma (HCC) is the fifth most common cancer world-wide, contributing to one third of all cancer-related deaths. Current treatment options for HCC include surgical resection, chemo- and radioembolization, transplantation, and stereotactic radiosurgery. The only approved pharmacological interventions for advanced disease include Sorafenib, a multi-tyrosine kinase inhibitor, in combination with doxorubicin. However, this treatment regime only extends recurrence-free survival by several months. In most cases, patients will succumb to the disease within a year following diagnosis. This highlights an urgent need to identify new therapeutic targets in HCC. Considerable evidence supports a role for de novo lipogenesis (DNL) in HCC development. However, this process has never been targeted in vivo in liver cancer. Herein we propose two Specific Aims that will evaluate the role of DNL in HCC initiation and progression. Aim 1 will test ethanol-induced tumor initiation and progression following carcinogen treatment (diethylnitrosamine) in a novel line of transgenic mice that lack hepatic expression of the rate limiting lipogenic enzymes acetyl-CoA carboxylases (ACC) 1 and 2. Aim 2 will evaluate how lipogenic nutrients in the diet contribute to HCC progression when combined with ethanol exposure. In this Aim we will also test the efficacy of a novel orally bioavailable ACC inhibitor to reduce tumor burden. Minimally, this project will determine whether ACC enzymes represent a pharmacological target for the treatment of HCC both with and without an ethanol stimulus. Maximally, we will identify ACC enzymes as new drug targets that can be pharmacologically inhibited in vivo to reduce liver tumor burden.